Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in Adjuvant Colorectal Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in Adjuvant Colorectal Cancer (NCT04034355), a randomized phase 3 study. The primary outcome is Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN).

2. Clinical Question

The study addressed prevention of chronic neuropathy associated with oxaliplatin in the adjuvant treatment of colorectal cancer. The primary endpoint classified a participant as having moderate or severe neuropathy if at least one of the first four items of the FACT/GOG-NTX-13 questionnaire received a score of 3 or 4. These items target numbness, tingling, or discomfort in the hands or feet. The registry also lists outcomes related to broader neuropathy severity, cold sensitivity, oxaliplatin exposure, vibration sensitivity, pain, hand function, and disease-free survival.

3. Trial Design

This was a phase 3, randomized, triple-masked, parallel-group, placebo-controlled study. Its official title describes it as multicenter and evaluates PledOx on top of modified FOLFOX6 in adjuvant colorectal cancer treatment. The registry lists enrollment of 301. The intervention was calmangafodipir at 5 µmol/kg; the comparison group received placebo, described as 0.9% sodium chloride.

The study began on 2019-01-07, and the primary completion date was 2020-08-31. Its status is terminated. The reason for termination is not reported in the registry record, so the status alone does not explain why the study stopped or what decisions followed. The registry record lists the sponsor as Egetis Therapeutics AB (publ).

The primary endpoint was assessed 9 months after the first dose of investigational medicinal product, administered on Day 1, Cycle 1 of modified FOLFOX6. The primary results use a modified intention-to-treat analysis set. The posted description says this set included patients meeting at least one of specified criteria, but the second criterion is cut off and the full definition is not reported in the registry record. The sponsor's analysis is described as a Cochran-Mantel-Haenszel analysis of a risk ratio. Further details of stratification, covariate adjustment, handling of missing endpoint assessments, and the trial's original sample-size justification are not reported in the registry record.

Randomization and masking are features of the design that can reduce some sources of bias, but the registry excerpt does not state how the randomization sequence was generated, how allocation was concealed, or which groups of people were masked. Those details are not reported in the registry record. The posted enrollment should not be treated as the number analyzed for every endpoint: the outcome-specific analysis sets differ, and the reasons for these differences are not fully described.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: 371 patients were screened in the 28 days before the start of treatment, 301 were randomised and 297 were treated.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria: * the patient was randomized prior to 1 Dec 2019 (i.e. the patient was eligible for at least 3 months of IMP) and had at least one post-baseline assessment for efficacy, or * the 3 month Assessment Visit occurred prior to 1 Mar 2020, or * the patient received the 6th cycle of IMP after 1 Mar 2020.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Safety analysis set consisting of all randomized patients who received at least one dose of IMP. Patients were analyzed according to the study treatment they actually received.

6. Primary Endpoint

The registry lists the primary outcome as Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN), measured over 9 months.

The primary endpoint is the number and percentage of participants classified as having moderate or severe chronic chemotherapy-induced peripheral neuropathy 9 months after the first dose of study treatment. Classification was based on the FACT/GOG-NTX-4, a four-item subscale within the FACT/GOG-NTX-13 questionnaire. A participant met the endpoint if at least one of the first four items was scored 3 or 4. The items target numbness, tingling, or discomfort in the hands or feet.

The wider questionnaire asks about the severity and impact of neurotoxicity symptoms over the past 7 days. Each item can be rated from 0, “not at all,” to 4, “very much”; higher total scores indicate a worse outcome. The primary endpoint uses a threshold on a subset of items rather than the questionnaire's full total score. That threshold makes the outcome a binary classification: each participant either meets the endpoint definition or does not.

Patient-reported symptoms are relevant to neuropathy because they capture experiences such as tingling and numbness that may affect daily life. A threshold-based endpoint can be easier to interpret as a proportion of participants meeting a specified symptom criterion, though it does not convey the full range or change in symptom severity. The registry record does not report why this particular threshold or assessment time was selected.

7. Results Posted in the Registry

• PledOx (5 µmol/kg): 56.7% (68/120) versus 38.7% (46/119) on control; risk difference 18.0 percentage points (95% CI 5.6 to 30.5), risk ratio 1.47 (1.11–1.93); unadjusted two-proportion z-test p = 0.005.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • PledOx (5 µmol/kg): 74.2% (89/120) versus 62.2% (74/119) on control; risk difference 12.0 percentage points (95% CI 0.3 to 23.7), risk ratio 1.19 (1.00–1.42); unadjusted two-proportion z-test p = 0.047.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for PledOx (5 µmol/kg) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Vibration Sensitivity on the Lateral Malleolus

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • PledOx (5 µmol/kg): mean -1.38 versus -1.43 on control; difference 0.05 (95% CI -0.41 to 0.51), standardized effect d = 0.03; z-test p = 0.832.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between PledOx (5 µmol/kg) and the control. The interval gives the range of effects that remain compatible with the data.

Functional Impairment (in the Non-dominant Hand)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • PledOx (5 µmol/kg): mean 16.23 versus -0.39 on control; difference 16.62 (95% CI 4.23 to 29.01), standardized effect d = 0.36; z-test p = 0.009.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for PledOx (5 µmol/kg) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes do not present a single consistent pattern that independently reinforces the primary endpoint. The broader neuropathy classification points in the same general direction as the primary symptom-threshold result, while the continuous measures are less uniform: one estimate is near zero and imprecise, and another is positive with an interval that excludes zero. These results concern different constructs and measurement scales, so agreement or disagreement should not be reduced to a simple vote across endpoints.

The registry lists seven secondary outcomes, but numerical results are posted for only some of them. Results for cold-item sensitivity, oxaliplatin cumulative dose, worst pain in hands or feet, and disease-free survival are not reported in the registry record. The available secondary analyses cannot therefore be treated as a complete account of all outcomes listed for the study. Nor does the posted information establish why some results are absent.

Secondary endpoints can help describe the breadth of observed outcomes and suggest questions for further evaluation, but they generally carry less confirmatory weight than a prespecified primary endpoint. Multiple outcomes create opportunities for chance findings, especially where no multiplicity procedure or testing hierarchy is reported. The record does not state that secondary p-values were adjusted. Accordingly, these results should be considered exploratory and interpreted with attention to their distinct measurement properties, uncertainty, and incomplete reporting, rather than used to overturn or independently confirm the primary analysis.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy
• Sensitivity to Touching Cold Items
• Cumulative Dose of Oxaliplatin During Chemotherapy
• Vibration Sensitivity on the Lateral Malleolus
• Worst Pain in Hands or Feet
• Functional Impairment (in the Non-dominant Hand)
• Patients With Disease Free Survival

9. Statistical Interpretation

10. Statistical Methods Explained

Binary endpoint and risks. The primary outcome is binary because each participant is classified as meeting or not meeting the stated neuropathy threshold. The arm-specific proportions describe the observed risk of meeting that definition within each analysis group. The posted counts are 68 of 120 for PledOx and 46 of 119 for placebo. A risk difference expresses the absolute contrast between these proportions; the unadjusted estimate is 0.180. A risk ratio expresses their relative contrast; the sponsor's reported adjusted estimate is 1.521. These measures answer related but distinct questions, so their numerical values are not directly comparable.

Uncertainty and hypothesis tests. A confidence interval gives a range of estimates compatible with the data and the method used, subject to its assumptions. The primary unadjusted risk-difference interval is 0.056 to 0.305. The sponsor-reported risk-ratio interval is 1.046 to 2.211. The null value is zero for a difference and one for a ratio. A p-value measures compatibility between the observed data and a specified null model; it is not the probability that the null is true, nor does it measure the size or clinical importance of an effect. The unadjusted primary p-value is 0.005, and the sponsor-reported p-value is 0.028.

Adjusted versus unadjusted comparisons. The sponsor reports a Cochran-Mantel-Haenszel analysis for the risk ratio. This method can combine information across strata to produce an adjusted association, but the registry record does not report the strata or enough details to reconstruct the analysis. The recalculated risk difference is a simple unadjusted calculation from posted summary counts. It does not reproduce the sponsor's method or incorporate any stratification. Because the methods and effect measures differ, numerical disagreement would not by itself imply an error; the registry marks no discrepancy. The sponsor's reported analysis remains the official analysis in the record, while the unadjusted calculation offers a transparent complementary summary.

Continuous outcomes. The secondary measures of vibration sensitivity and functional impairment are reported as means with standard deviations. A mean difference compares the arm averages; a standard deviation describes variability among participant measurements, not uncertainty in the mean itself. For vibration sensitivity, the recalculated mean difference is 0.05, with a 95% confidence interval from -0.412 to 0.512 and p = 0.832. For functional impairment, the mean difference is 16.62 seconds, with a 95% confidence interval from 4.232 to 29.01 and p = 0.009. These are unadjusted recalculations from posted summary statistics, and the registry lists no sponsor-reported analyses for these outcomes. The record does not provide sufficient scoring detail to assign a clinical interpretation to the direction of each continuous measure.

Multiplicity and interpretation. The registry lists eight outcome measures and seven secondary outcomes. When several outcomes are analyzed, the chance of at least one apparently notable result can increase if each is tested separately without adjustment. The record does not report a multiplicity adjustment or identify a prespecified hierarchy for the secondary endpoints. This does not make the findings meaningless, but it means individual unadjusted secondary p-values should be treated cautiously and not as equivalent to a primary confirmatory test.

Over-dispersion and model choice. For count or binary outcomes, statistical models rely on assumptions about the variability and structure of the data. General statistical principle: if variability is greater than the model allows, standard errors can be too small and confidence intervals too narrow. The primary endpoint is a participant-level binary outcome, and the registry reports a risk-ratio analysis; it does not report an over-dispersion assessment or model diagnostics. No conclusion about such diagnostics can be drawn from the posted record.

Planning illustrations. Sample-size illustrations based on observed effects are not the same as the original design calculation. Their assumptions are listed with the planning results: two-sided significance level 0.05, equal allocation between the two arms, and a normal approximation, with the target effect expressed as a stated fraction of the observed effect. The original design assumptions and sample-size justification are not reported in the registry record. These planning calculations are hypothetical and do not represent observed power.

11. Confidence Intervals and Precision

Precision concerns how much uncertainty surrounds an estimate. The primary unadjusted risk difference is 0.180, and its 95% confidence interval runs from 0.056 to 0.305. The interval excludes zero, the null value for a risk difference, but it spans a range of possible contrasts rather than identifying one exact value. Its width is relevant when judging how precisely the absolute difference has been estimated.

The sponsor's reported risk ratio is 1.521, with a 95% confidence interval from 1.046 to 2.211. The interval excludes one, the ratio's null value, while still allowing a range of relative associations. The sponsor's ratio and the unadjusted difference use different scales and analytic methods, so their intervals should not be compared as though they measured the same quantity.

For the secondary continuous outcomes, the vibration-sensitivity interval ranges from -0.412 to 0.512 and includes zero. The functional-impairment interval ranges from 4.232 to 29.01 and excludes zero. These recalculations are unadjusted and do not account for the broader set of outcomes. For the secondary binary neuropathy endpoint, the risk-difference interval ranges from 0.003 to 0.237. Confidence intervals describe uncertainty under the method's assumptions; they do not account for possible bias, incomplete outcome data, or an unreported multiplicity strategy.

Precision is also affected by how many participants contribute to an outcome and by the variability of the measurements. The endpoint-specific analysis counts vary, and the registry record does not fully explain missing assessments or the differing analysis populations. The intervals therefore need to be read alongside the limitations in the record, not as a complete measure of uncertainty about the treatment effect.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm for the binary and continuous outcomes in this trial. They are not totals across both arms and are not event totals. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The assumed effect is a stated fraction of the observed effect. The trial's own original design assumptions and sample-size justification are not reported in the registry record.

The 80% power column gives the illustrative participants per arm for a planned study to have an 80% probability of detecting the selected effect under the stated assumptions, if that effect and those assumptions were correct. The 90% power column gives the corresponding planning target for a 90% probability. Higher target power generally requires a larger planned sample. The rows for 75% and 50% of the observed effect illustrate that smaller effects require more participants per arm than planning around the full observed effect.

These numbers are planning illustrations based on effects observed in the current results, not a reconstruction of the original study design. They are not observed power and do not establish whether the completed trial was adequately powered. The sample-size curve is best read as a visual expression of how the illustrative requirement changes as the target effect becomes smaller; it should be interpreted under the same assumptions and not as a forecast of the outcome of another trial.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.387; treatment proportion p₁ = 0.567; average p̄ = 0.477.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7063 = 1.3844.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6948 = 0.5847.
4. n = (1.3844 + 0.5847)² / (0.1801)² = 119.5, rounded up to 120 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.38655462184874                          # control proportion
p1 <- 0.566666666666667                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(4034355)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 120 (80% power), 160 (90% power)
 75% of observed effect: n per arm = 213 (80% power), 284 (90% power)
 50% of observed effect: n per arm = 474 (80% power), 634 (90% power)
power.prop.test: 119.5 
Simulated power at n = 120 per arm: 0.789 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The sponsor's reported primary analysis is a Cochran-Mantel-Haenszel risk ratio of 1.521, with a 95% confidence interval from 1.046 to 2.211 and p = 0.028. The registry does not provide the strata or full model details, so the calculation cannot be independently reconstructed from the posted summary. The result is the sponsor's analysis as recorded in the registry.

The recalculated result is an unadjusted risk difference of 0.180, with a 95% confidence interval from 0.056 to 0.305 and p = 0.005. It is calculated directly from the posted arm counts and uses an absolute contrast rather than a relative one. The registry indicates no discrepancy. The two estimates are therefore complementary summaries rather than competing versions of the same analysis: they use different measures and, for the sponsor result, a different analytic approach.

The unadjusted calculation should not be read as a correction to the sponsor's analysis or as a replacement for it. The sponsor result is the registry-reported inferential analysis; the recalculation helps make the absolute contrast visible using the posted counts. Neither result alone resolves questions about missing data, multiplicity, the analysis population's full definition, or the unreported design and analysis details.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and seven secondary outcomes. Testing several outcomes can increase the chance that at least one result appears statistically notable by chance when each is assessed separately. A multiplicity strategy might control this risk by adjusting significance thresholds or specifying an ordered testing procedure. Such a strategy, and any prespecified hierarchy among secondary outcomes, are not reported in the registry record.

The registry's primary endpoint population is described as a modified intention-to-treat analysis set, with inclusion criteria beginning with patients randomized before 1 Dec 2019 and an alternative criterion involving a 3 month assessment. The criterion is truncated, so the full population definition is not reported in the registry record. The exact approach to missing primary endpoint assessments, imputation, or sensitivity analyses is also not reported. As a result, it is not possible to assess from this record whether missingness could have affected the arm comparison.

Analysis denominators vary across endpoints. The primary outcome includes 120 participants in the PledOx group and 119 in the placebo group, while continuous endpoints have different reported counts. The record does not fully explain these differences or establish whether they reflect missing measurements, eligibility rules, or other analysis-set decisions. The overall enrollment figure should therefore not be assumed to be the denominator for each outcome.

The registry does not report the original sample-size justification, planned interim analyses, or a complete statistical analysis plan. It also does not report enough detail to evaluate whether outcome definitions and analysis choices were finalized before results were available. These omissions limit assessment of selective reporting and the confirmatory status of secondary analyses; they do not establish that such problems occurred.

16. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: infusion related reaction (2.0%), anaphylactic reaction (1.4%), pulmonary embolism (1.4%), sudden hearing loss (0.7%), colitis (0.7%).

The registry reports serious adverse events for the PledOx and placebo safety groups, with 147 and 150 participants at risk, respectively. Serious adverse events affected 20 participants in each group. Other adverse events affected 146 participants in each group. The registry also records 1 death in each group. These figures describe the posted safety counts; they do not establish whether an event was caused by study treatment, and the record excerpt does not provide event-level details or a causal assessment.

The most frequently listed serious-event terms include infusion related reaction at 2.0%, anaphylactic reaction at 1.4%, pulmonary embolism at 1.4%, sudden hearing loss at 0.7%, colitis at 0.7%, and ileus at 0.7%. These percentages are reported as registry values. The record does not provide enough information in this summary to assess timing, severity beyond the serious-event classification, duration, or the relationship of each event to treatment.

Safety counts should be read separately from the efficacy analysis population. The safety groups have different at-risk counts from the primary endpoint analysis sets, and the registry does not explain the difference in detail. The posted figures alone do not permit a complete comparative safety assessment.

17. What the Result Does, and Does Not, Mean

The primary results describe a higher observed frequency of moderate or severe chronic neuropathy at 9 months in the PledOx group than in the placebo group, using the registry's stated symptom threshold. The unadjusted risk-difference interval excludes zero, and the sponsor's reported risk-ratio interval excludes one. These statistical findings characterize the posted analysis; they do not by themselves establish that PledOx caused the difference or explain its clinical importance.

The endpoint is a questionnaire-based classification of symptoms over the past 7 days at a specified follow-up time. It does not summarize every aspect of neuropathy, the full range of symptom burden, or the long-term course beyond the assessment reported. Other outcomes listed in the registry include pain, sensory measures, hand function, cumulative oxaliplatin dose, and disease-free survival, but numerical results for several are not reported in the registry record.

The results also do not establish how applicable the findings are to patients outside the study's stated Stage III or high-risk Stage II colorectal cancer population receiving adjuvant treatment. The full modified intention-to-treat definition is truncated, and the record does not provide complete information on missing outcome data, multiplicity, or the original statistical plan. These limitations affect how confidently the estimates can be generalized or interpreted as confirmatory.

Finally, the terminated status is not an efficacy conclusion. The reason for termination is not reported in the registry record. The posted data should therefore be understood as registry results with measurable uncertainty and reporting limitations, rather than a complete account of the trial's conduct or a basis for medical advice.

18. Why This Trial Matters Statistically

This trial is statistically notable because its primary endpoint is a participant-level symptom classification, while its reported analyses include both an absolute risk difference and a sponsor-reported relative risk. Seeing both measures helps distinguish the size of the observed absolute contrast from the relative comparison. The estimates answer different questions and should be interpreted with their own confidence intervals and analytic assumptions.

The registry also illustrates why a nominally notable primary result does not settle every interpretive question. The analysis population is modified intention-to-treat, but its full definition is truncated. Outcome-specific denominators differ, and the record does not fully explain missing assessments. The sponsor's analysis method is named, but the information needed to reproduce its stratified analysis is not reported. These are practical limits on independent assessment, even when the posted counts and estimates are clear.

Secondary outcomes provide a broader view of symptoms and function, yet the available results are incomplete and cover multiple measures. Without a reported multiplicity approach, individual secondary findings deserve less weight than a prespecified primary test. The planning illustrations further show how required sample sizes depend on the assumed effect: smaller target effects require more participants per arm. Because these illustrations use the observed effects and are not the trial's original design calculation, they cannot explain the trial's enrollment or prove its power.

Together, these features make the record useful for teaching the distinction between observed results, adjusted sponsor analyses, unadjusted recalculations, uncertainty, and reporting completeness. They also show why statistical significance should be considered alongside design and analysis transparency rather than treated as a complete interpretation.

19. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several limitations are specific to the registry information for this trial. The study is marked terminated, but the reason for termination is not reported in the registry record. The primary analysis population description is cut off, preventing a complete assessment of its eligibility criteria. The registry does not provide a full account of missing outcome data, exclusions, or the differing denominators across efficacy outcomes.

The sponsor's primary analysis is identified as Cochran-Mantel-Haenszel, but the relevant strata and full analytic details are not reported. The original sample-size justification, interim analyses, and complete statistical analysis plan are also not reported. These absences limit evaluation of the prespecification and reproducibility of the analyses; they do not show that the analyses were conducted improperly.

Numerical results are not reported for several listed secondary outcomes, including cold-item sensitivity, cumulative oxaliplatin dose, worst pain in hands or feet, and disease-free survival. Without these results, the secondary-outcome picture is incomplete. No multiplicity adjustment or testing hierarchy is reported, so individual unadjusted secondary findings should not be regarded as independent confirmatory evidence.

The safety summary gives aggregate counts and selected serious-event terms, but does not include enough detail to assess timing, duration, event-level severity, or treatment relationship. The registry record also does not explain the difference between safety and efficacy analysis populations. These constraints mean that neither the efficacy nor the safety summaries should be treated as a complete account of the trial.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in Adjuvant Colorectal Cancer — NCT04034355.
• Registry record last updated 2022-01-26; status last verified 2021-11.
• Results first posted 2022-01-26.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

23. Record Summary

NCT04034355 is a randomized, triple-masked, parallel-group phase 3 study of calmangafodipir (PledOx) at 5 µmol/kg versus placebo, used with modified FOLFOX6 in adjuvant treatment for Stage III or high-risk Stage II colorectal cancer. The registry lists enrollment of 301, a start date of 2019-01-07, primary completion on 2020-08-31, and status as terminated.

The primary endpoint was moderate or severe chronic chemotherapy-induced peripheral neuropathy at 9 months, defined using a threshold on the FACT/GOG-NTX-4. The posted counts were 68 of 120 for PledOx and 46 of 119 for placebo. The sponsor reported a Cochran-Mantel-Haenszel risk ratio of 1.521, with a 95% confidence interval from 1.046 to 2.211 and p = 0.028. Important details, including the full primary analysis population definition, reason for termination, and original design assumptions, are not reported in the registry record.